title: [Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization].
abstract: Dopamine transporter (DAT) internalization is a mechanism underlying the decreased dopamine reuptake caused by addictive drugs like methamphetamine (METH). We found that Piccolo, a presynaptic scaffolding protein, was overexpressed in the nucleus accumbens (NAc) of the mice repeatedly administrated with METH. Piccolo downexpression by antisense technique augmented METH-induced behavioral sensitization, conditioned reward and synaptic dopamine accumulation in NAc. Expression of Piccolo C2A domain attenuated METH-induced inhibition of dopamine uptake in PC12 cells expressing human DAT. Consistent with this, it slowed down the accelerated DAT internalization induced by METH, thus maintaining the presentation of plasmalemmal DAT. In immunostaining and structural modeling Piccolo C2A domain displays an unusual feature of sequestering membrane phosphatidylinositol 4,5-bisphosphate, which may underlie its role in modulating DAT internalization. Together, our results indicate that Piccolo upregulation induced by METH represents a homeostatic response in the NAc to excessive dopaminergic transmission. Piccolo C2A domain may act as a cytoskeletal regulator for plasmalemmal DAT internalization, which may underlie its contributions in behavioral plasticity.
authors.affiliation: Department of Pharmaceutical Therapy & Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hibi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D008694:Methamphetamine; D051379:Mice; D009479:Neuropeptides / Q000502:physiology*; D019966:Substance-Related Disorders / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D009479:Neuropeptides; C498631:Pclo protein, mouse; D008694:Methamphetamine